While transforming growth factor-? (TGF-?) has a dual tumor suppressor/tumor promoter role in tumorigenesis, the role of other TGF-? superfamily ligands, including the bone morphogenetic proteins (BMPs), is just being defined. TGF-? superfamily ligands utilize a signaling coreceptor, the type III TGF-? receptor (T?RIII), to mediate and regulate ligand binding and signaling through the type I and type II TGF-? superfamily receptors. T?RIII also undergoes ectodomain shedding to produce a natural soluble form of T?RIII (sT?RIII), which we have detected in human plasma. We have recently established that T?RIII also functions as a BMP co-receptor and is required for some BMP-mediated biology, and that T?RIII and BMP have roles in pancreatic cancer EMT and progression. To investigate the mechanism of T?RIII function in human pancreatic cancer the following hypothesis is proposed: BMPs have dichotomous effects on pancreatic cancer progression, with loss of autocrine BMP responsiveness, in part through loss of T?RIII expression and decreased ALK-6 signaling, facilitating cancer initiation and elevated BMP levels, in part through loss of sT?RIII expression, then promoting cancer progression through EMT-mediated increases in cellular motility and invasiveness. This hypothesis will be addressed by four Specific Aims. Specific Aim1: The mechanism by which T?RIII orchestrates the relative bioactivity of TGF-? superfamily ligands in pancreatic cancer will be explored by defining the structural determinants mediating T?RIII ligand binding to BMP, determining the relative ligand binding hierarchy of TGF-? superfamily ligands to T?RIII and sT?RIII, establishing whether sT?RIII serves as an antagonist of BMP signaling and whether the relative expression of T?RIII and sT?RIII regulate the cellular effects of TGF-? superfamily ligands in pancreatic cancer cells. Specific Aim2: The mechanism by which T?RIII selectively increases BMP signaling through ALK-6 will be established by defining whether T?RIII selectively mediates the interaction of ALK-6 with ?-arrestin2 to selectively mediate the internalization of ALK-6 and establishing whether T?RIII mediated ALK-3/ALK-6 internalization is necessary for BMP signaling and BMP-mediated biology. Specific Aim3: The levels of cell surface T?RIII, circulating sT?RIII and circulating active TGF-? superfamily members will be established in murine models and human specimens to establish whether these levels are coordinately regulated during pancreatic cancer progression. Specific Aim4: The effect of increasing or decreasing T?RIII and/or sT?RIII expression in murine pancreatic cancer models of initiation and progression will be established to define whether T?RIII and/or sT?RIII have opposing effects on pancreatic cancer initiation and progression. These studies will define the mechanism by which T?RIII orchestrates TGF-? superfamily signaling to regulate the initiation and progression of pancreatic cancer, define the biological implications of T?RIII ectodomain shedding in the context of pancreatic cancer and aid in targeting these pathways for the prevention and treatment of human cancers. PUBLIC HEALTH RELEVANCE: We have demonstrated that a cell surface receptor for transforming growth factor-? (TGF-?) superfamily ligands, the type III TGF-? receptor (T?RIII), is able to suppress cancer progression in a broad spectrum of human cancers, including cancers of the breast, lung, ovary, pancreas and prostate, by decreasing the ability of the cancer cells to migrate, invade and spread to distant sites. We have also recently established that T?RIII is able to bind and regulate signaling of another subfamily of TGF-? superfamily ligands, the bone morphogenetic proteins (BMPs), and that both T?RIII and BMPs have a role in pancreatic cancer progression. Thus, these studies where we will investigate mechanisms by which T?RIII regulates TGF-?2 superfamily ligand function in pancreatic cancer are important to perform and relevant to public health as these mechanistic insights will define the biological functions of T?RIII in the context of human pancreatic cancers, increase understanding of the role of TGF-? superfamily signaling and of T?RIII in regulating tumor biology, and aid in targeting TGF-? superfamily signaling pathways for the treatment of cancers and other diseases in which TGF-? superfamily signaling pathways have a prominent role.